Arizona Cardinals vs San Francisco 49ers Picks and Predictions for Sunday, September 21, 2025

Arizona Cardinals vs San Francisco 49ers Game Information

The Arizona Cardinals will be on the road again this week with a game in San Francisco against the 49ers in Levi’s Stadium at 4:25 PM. Arizona is undefeated through two games this season following its five-point victory against the Carolina Panthers a week ago. The San Francisco 49ers will be at home for the first time this week, undefeated through two games after a narrow 5-point victory in New Orleans against the Saints last week. The NFL action is starting to pick up and that means you want some winners and you can find that with our free NFL Picks.

Arizona Cardinals Preview

The Arizona Cardinals have been stout through their first two games of the season, averaging 23.5 points per game. Defensively, Arizona has done the work as well, holding opponents to 17.5 points through two games played. Kyler Murray leads the Arizona offense this season with 383 yards and three scores on 38 completions. Trey Benson is the top ball carrier on the team with 83 yards on 11 carries. Trey McBride leads the team with 139 yards on 12 receptions.

San Francisco 49ers Preview

The San Francisco 49ers have been stout through their first two games of the season, averaging 21.5 points per game overall. Defensively, San Francisco has halted their opponents, allowing just 12 points per game through two games played. Mac Jones has led the charge for the San Francisco offense this season with 279 yards and three scores on 26 completions through one game. Brock Purdy has 277 yards and two touchdowns on 26 completions this season. Christian McCaffrey leads the team with 124 yards on 35 carries. Ricky Pearsall is the top receiver on the team with 164 yards on 8 receptions.

Arizona Cardinals vs San Francisco 49ers Game Prediction

Both teams are playing well coming into this week, as each is undefeated through two games played. Look for San Francisco to thrive in front of their home fans this week against a good Arizona team. Take the 49ers to continue their winning ways as they get the home winning cover this week against Arizona. Final Score Prediction, San Francisco 49ers win and cover 27-21.

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 Cardinals vs 49ers Best Picks

• San Francisco 49ers +1.5
• Over 44.5